Abstract:
:Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.
journal_name
Nat Genetjournal_title
Nature geneticsauthors
Lunardi A,Ala U,Epping MT,Salmena L,Clohessy JG,Webster KA,Wang G,Mazzucchelli R,Bianconi M,Stack EC,Lis R,Patnaik A,Cantley LC,Bubley G,Cordon-Cardo C,Gerald WL,Montironi R,Signoretti S,Loda M,Nardella C,Pandolfidoi
10.1038/ng.2650subject
Has Abstractpub_date
2013-07-01 00:00:00pages
747-55issue
7eissn
1061-4036issn
1546-1718pii
ng.2650journal_volume
45pub_type
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